WO2005012293A1 - Composes de phenylazole, leur procede de production et antioxydants - Google Patents

Composes de phenylazole, leur procede de production et antioxydants Download PDF

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Publication number
WO2005012293A1
WO2005012293A1 PCT/JP2004/011297 JP2004011297W WO2005012293A1 WO 2005012293 A1 WO2005012293 A1 WO 2005012293A1 JP 2004011297 W JP2004011297 W JP 2004011297W WO 2005012293 A1 WO2005012293 A1 WO 2005012293A1
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group
formula
substituted
atom
optionally substituted
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PCT/JP2004/011297
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English (en)
Japanese (ja)
Inventor
Nobuhiro Umeda
Nobuo Mochiduki
Seiichi Uchida
Mitsumasa Takada
Seiichi Ikeyama
Shiro Tsubokura
Yasuyuki Shiinoki
Fumie Shirato
Hiroko Moroe
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Nippon Soda Co., Ltd.
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Priority to JP2005512591A priority Critical patent/JP4377881B2/ja
Priority to EP04748268A priority patent/EP1650206A4/fr
Priority to US10/566,820 priority patent/US7553837B2/en
Priority to AU2004260758A priority patent/AU2004260758B2/en
Priority to CA002534263A priority patent/CA2534263A1/fr
Publication of WO2005012293A1 publication Critical patent/WO2005012293A1/fr
Priority to US12/466,919 priority patent/US20090306055A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a novel phenylazole compound, a method for producing the same, an antioxidant containing the compound as an active ingredient, and a retinal oxidation inhibitor, a lipoxygenase inhibitor, a 20-HETE production inhibitory rate,
  • the present invention relates to a drug for treating diseases, cerebrovascular or circulatory diseases, and a drug for treating cerebral infarction.
  • Patent Document 2 an imidazole compound having an antihyperlipidemic effect and useful for treatment and prevention of arteriosclerosis
  • Patent Document 3 a benzothiazine lipoxamide represented by the following formula having anti-arthritic activity
  • Lipoxygenases that add oxygen to unsaturated fatty acids such as arachidonic acid include 5-LO, 8-L ⁇ , 12-LO, and 15-LO depending on the oxygenation site.
  • 5-LO is the first enzyme to synthesize leukotriene, a powerful inflammatory mediator.
  • Leukotrienes are involved in various inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and psoriasis, and their control is useful for treatment of these diseases.
  • 12-LO and 15-LO react with linoleic acid, cholesterol esters, phospholipids, and low-density lipoprotein (LDL) in addition to arachidonic acid, and oxygenate the unsaturated fatty acids.
  • LDL low-density lipoprotein
  • HETE Hydroxyeicosatetraenoic acid
  • 20—HETE is known to contract or expand microvasculature and induce cell proliferation in major organs such as kidney and cerebral blood vessels, and is involved in important physiological actions in vivo, such as renal disease, brain It has been suggested that it is deeply involved in pathological conditions such as vascular diseases and cardiovascular diseases. Furthermore, it has been reported that a phenylazole derivative has an inhibitory effect on 20-HETE synthase.
  • oxidative stress related to free radicals / reactive oxygen is considered as one of the causes of many eye diseases such as cataract and macular degeneration that frequently occur with aging.
  • eye tissues the retina is known to be susceptible to aging along with the lens.
  • the retina is rich in higher unsaturated fatty acids, is nourished by both retinal and choroidal vessels, and is susceptible to various free radicals due to its high oxygen consumption.
  • the light received is representative of oxidative stress on the retina. Visible rays and infrared rays occupy the majority of sunlight reaching the ground, and ultraviolet rays, which are contained in a few percent, have a greater interaction with living organisms than visible rays and infrared rays, and have a greater effect on health.
  • UV-A 320-400 nm
  • UV-B 280-320 mii
  • UV-C (190-280 nm)
  • UV-A 320-400 nm
  • UV-B 280-320 mii
  • UV-C (190-280 nm)
  • Age-related macular degeneration is a highly blinded retinal disorder among eye diseases.In the United States, 100,000 people have mild symptoms and more than 450,000 have visual impairment caused by the disease. It is said to have. In Japan, which is entering a rapidly aging society, there is a concern that this disease will increase. Although the mechanism of the onset of macular degeneration is largely unknown, it has been pointed out that the progression of this lesion involves a peroxidation reaction due to light absorption in the retina. In the early stage of the disease, the appearance of a lipofuscin-like fluorescent substance called dollarase has been observed, and lipofuscin is a secondary degradation product of lipid peroxide.
  • a therapeutic agent for retinal diseases containing a specific dihydrofuran derivative useful for the prevention and treatment of retinal diseases due to such antioxidant action, propionyl L-carnitine or a pharmacologically acceptable salt, and a retina containing carotenoids Drugs for visual and retinal changes including macular degeneration are known.
  • Patent Literature 1 Japanese Patent Application Laid-Open No. 2_1-1995
  • Patent Document 2 International Publication No. 95 / 29-163 Pamphlet
  • Patent Document 3 German Patent Application Publication No. DE 3,407,505
  • Patent Document 4 Japanese Patent Application Laid-Open No. 55-695667
  • Patent Document 5 Japanese Patent Application Laid-Open No. 5-14014
  • Patent Literature 6 International Publication No. 0/0 0 6550 Pamphlet
  • Patent Document 7 International Publication No. WO 96/284337 Pamphlet
  • Patent Document 8 Japanese Patent Application Laid-Open No. 6-222813 Disclosure of Invention:
  • the present invention provides an antioxidant effective for treating ischemic organ damage such as arteriosclerosis, myocardial infarction, and cerebral infarction, or for treating diseases caused by oxidative cell damage such as renal disease.
  • ischemic organ damage such as arteriosclerosis, myocardial infarction, and cerebral infarction
  • diseases caused by oxidative cell damage such as renal disease.
  • lipoxygenase inhibitor, 20-HETE synthase inhibitor, renal disease, cerebrovascular or cardiovascular disease therapeutic agent, and cerebral infarction therapeutic agent for suppressing retinal damage due to photooxidation As an issue.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result of the fact that the efficacy of existing antioxidants is not enough, the drug does not reach the target site or the activity is inactivated before reaching the target site.
  • intensive studies aimed at developing antioxidants that have better organ transportability, especially that can easily cross the blood-brain barrier or the blood-retinal barrier, the compound represented by formula (1)
  • the intended purpose has been achieved.
  • they have found that they have excellent in vivo antioxidant activity regardless of the administration route, and have completed the present invention.
  • the present inventors studied the effect on the retina by irradiating rat eyes with a fixed dose of UV-A to the retina.
  • lipofuscin-like fluorescent substances are often detected due to the reaction product of lipid peroxide-derived aldehydes and proteins.
  • An increase in the protein around 66 kDa was observed, which is in direct proportion to the change in the retinal tissue of the UV-A-irradiated eye.
  • This protein was found to be an albumin-like substance based on the results of instrumental analysis and studies using albumin-free rats. It recognized. Under invitro, in the autoxidation reaction of the retinal tissue, the presence of albumin significantly increased the amount of liposuftin-like fluorescent substance, indicating that some proteins in the retinal tissue due to UV-A irradiation were abnormal.
  • the increase is associated with an increase in fluorescent material in the retina and is likely to trigger retinal damage.
  • the present inventors have studied a retinal disorder inhibitor using the change in retinal protein as a first biochemical index. During this process, it was confirmed that the proprietary compound having a strong antioxidant ability was transferred to the retina in a short time by oral administration, and markedly suppressed the increase of 66 kDa protein due to UV-A spot irradiation. These results indicate that the proprietary compound is effective against oxidative retinal damage, and in particular, is effective in reducing the progression and symptoms of age-related macular degeneration of the retina, which increases with aging. Thus, the present invention has been completed based on such knowledge.
  • B-D-Z (1) [wherein B represents the following formula (B-1), (B-2) or (B-3),
  • A represents an imidazolyl group or a pyrazolyl group represented by the following formula (A-1), (A-2), (A-3) or (A-4), and when B is (B-3) Is a hydrogen atom or 1 ⁇ May be expressed,
  • R 4 and R 5 may be each independently substituted with G 1 — 6-alkyl group, optionally substituted with G 1 alkoxy group, substituted with G 1 May be an alkylsulfonyl group, representing an octogen atom
  • R and 6 are a hydrogen atom, a C i 6 alkyl group optionally substituted with G 1, an optionally substituted G 1 _ 6 alkylcarbonyl group
  • G 1 represents a benzoyl group or a tetra-hydrobiral group which may be substituted
  • G 1 represents a cyano group, a formyl group, a hydroxyl group, an alkoxy group, an amino group, a monomethylamino group, a dimethylamino group or a halogen atom,
  • s represents 0 or an integer of 1 to 3
  • t represents an integer of 0, 1 or 2
  • R 4 or R 5 may be the same or different.
  • R i is a halogen atom, a nitro group, a cyano group, a hydroxyl group, and may be substituted with G 2 — a 6-alkyl group, a C ⁇ 6 alkoxy group which may be substituted with G 2, and a group substituted with G 2 May be substituted with an alkylthio group or G 2
  • R 2 represents an optionally substituted with G 2 ( ⁇ _ 6 alkyl group
  • R 3 is a hydrogen atom, an alkyl group optionally substituted with G 2, an optionally substituted G 2 ( ⁇ -6 alkylcarbonyl group, a benzoyl group optionally substituted with G 2, or G represents a benzyl group optionally substituted with 2,
  • G2 is a cyano group, formyl group, hydroxyl group, alkoxy group, alkoxycarbonyl group, nitro group, amino group, monomethylamino group, dimethylamino group
  • n 0 or any integer of 1 to 4, and when m is 2 or more, may be the same or different;
  • n 0 or any integer from 1 to 10, and when n is 2 or more, R 2 and R may be the same or different;
  • o represents an integer of 1 or 2
  • p represents 0 or an integer of 1 to 4, and when p is 2 or more, may be the same or different;
  • q, and r each independently represent an integer of 1 or 2
  • the dotted line represents a single bond or a double bond, and it is unlikely that a double bond will occur at the same time.
  • Y represents a substituent that satisfies the valence or a carbon atom or a nitrogen atom that may have a multiple bond
  • E represents an oxygen atom, a sulfur atom or the following formula (la);
  • R 6Q represents a hydrogen atom, a Ci 6 alkyl carbonyl group, (which may be substituted with a nitro group, a halogen atom, a hydroxyl group, an alkoxy group, or an alkyl group), a benzoyl group
  • R 7 and R 8 are each independently a hydrogen atom, Xia amino group, a hydroxyl group, a halogen atom, - 6 alkyl group, C i 6 alkoxy group, C 2 - 6 alkenyl group, C 2 6 alkynyl group, C 2 _ 6 Arukeniruo alkoxy group, C 2 6 Arukini Ruokishi group, C fi Ashiruokishi group, optionally substituted with G 2 C 3 6 Shikuroa A phenyl group, or a phenyl group which may be substituted with G 2;
  • j and k independently represent an integer of 0 or 1, and when B is (B-2), j and k represent 0;
  • R 7 and R 8 may be the same or different.
  • D represents an oxygen atom, a sulfur atom or the above formula (la),
  • X is an oxygen atom, Formula: SOu (where u represents an integer of 0, 1 or 2) or Formula: NR 9 (where R 9 is a hydrogen atom, and may be substituted with G 2 (Indicates a ⁇ -6 alkyl group or a benzyl group which may be substituted with G2.)
  • Z is a chroman-2-yl group substituted with G 3, a chroman-4-yl group substituted with G 3, a 2,3-dihydrobenzofuran-2-yl group substituted with G 3, G 2,3-dihydrobenzofuran substituted with 3-3-yl group, thiochroman-12-yl group substituted with G3, 2,3-dihydrobenzothiophene substituted with G3'- 2-yl group, thiochroman substituted with G3 4-yl group, 2,3-dihydrobenzothiophene-3-yl group substituted with G3, or 1,3-substituted with G3 Represents a 3-benzoxathiol-2-yl group,
  • G3 has the formula: NHR 10
  • R 1Q represents a hydrogen atom, a Ci- 6 alkylcarbonyl group, a nitro group, a halogen atom, a hydroxyl group, a 6 alkoxy group, or a benzoyl group which may be substituted with a —6 alkyl group.
  • R u represents a hydrogen atom, an alkyl Cal Poni group, (hydroxyl group, (: Bok 6 alkoxy group, a halogen atom, a C Bok 6 alkyl may be substituted with a group) Benzoi Le group.
  • Z is the following formula (Z-1), (Z_2), (Z-3), (Z-4) or (Z-5)
  • * represents an asymmetric carbon atom, represents an oxygen atom or a sulfur atom, and R 12 to R 32 each independently represent a hydrogen atom or a ( ⁇ 6 alkyl group, and G 3 represents Represents the same meaning as described above.
  • a therapeutic agent for circulatory diseases characterized by containing the antioxidant described in (3) and sixthly, a cerebral infarction characterized by containing the antioxidant described in (3).
  • a therapeutic agent for retinal oxidative disorders which comprises the antioxidant described in (3),
  • the therapeutic agent according to (8) wherein the retinal oxidative disorder is age-related macular degeneration or diabetic retinopathy.
  • Satetraenoic acid (20-HETE) is a synthase inhibitor.
  • the X-nilazole compound of the present invention or a pharmaceutically acceptable salt thereof is useful for treating ischemic organ damage such as arteriosclerosis, myocardial infarction, and cerebral infarction, or treating oxidative cell damage such as renal disease.
  • B-D-Z (1) [where B represents the following formula (B-1), (B-2) or (B-3),
  • A represents an imidazolyl group or a pyrazolyl group represented by the following formula (A-1), (A-2), (A-3) or (A-4), and when B is (B-3) May represent a hydrogen atom or 1 ⁇ ,
  • Puchirusuruhoniru ( ⁇ - 6 alkylsulfonyl group; fluorine, chlorine, bromine, halogen atom and iodine; represents, R 6 is A hydrogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-phenyl which may be substituted by G1 (: 6 alkyl groups such as n-hexyl, n-hexyl, etc .; methylcarbonyl, ethylcarbonyl, propyl group, An alkylcarbonyl group; a benzoyl group which may be substituted with G1, or a tetrahydropyranyl group;
  • G 1 is Shiano group; formyl group; a hydroxyl group; methoxy, ethoxy, Purobokishi, I Sopurobokishi, butoxy, sec- butoxy, isobutoxy, ( ⁇ _ 6 alkoxy group such as t- butoxy; Amino group; Monomechiruamino group; Jimechiruamino group Or halogen atoms such as fluorine, chlorine, bromine and iodine;
  • s represents 0 or any integer from 1 to 3
  • t represents an integer of 0, 1 or 2
  • R 4 or R 5 may be the same or different.
  • R 6 is a hydrogen atom
  • the imidazolyl group or pyrazolyl group represented by A can have the tautomeric structures shown below.
  • Preferred A is 1-H-imidazole-2-yl group, 1-H-imidazole-4-yl group, 1-pyrazole group, 1-methylimidazole-2-yl group, 1-methylimidazole-1 5-yl, 1-methylimidazole-4-yl, 1-methylpyrazole-4-yl, 1-imidazolyl, 1H-pyrazol-5-yl, 1H-pyrazole 4-yl group, 1-methylpyrazole-5-yl group, 1-methylpyrazole-3-yl group, 1-benzoylpyrazole-4-yl group, 1- (2-tetrahydroviranyl ) -Pyrazole-1-3-pyridyl group, more preferably A, includes a 1-imidazolyl group or a 1H-pyrazole-15-yl group bonded to the 3- or 4-position of the benzene ring.
  • Alkyl groups such as butyl, t-butyl, n-pentyl and n-hexyl; methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, t-butoxy, etc.
  • G 2 which may be substituted by G 2 of ( ⁇ _ 6 alkoxy group, optionally substituted with G 2 methylthio, Echiruchio, n- propylthio, isopropylthio, n- butylthio, Isobuchi Lucio, sec- Puchiruchio, t-Puchiruchio etc.
  • R 2 is C ⁇ such as methyl, ethyl, n-propyl, isopyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. — Represents a 6- alkyl group,
  • R 3 is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc.
  • a 6 alkyl group an alkyl group such as methylcarbonyl, ethylcarbonyl, propyl group, and butyl group optionally substituted with G2; a benzoyl group optionally substituted with G2; or G A benzyl group which may be substituted with 2;
  • G 2 is a cyano group; formyl group; hydroxyl group; methoxy, ethoxy, propoxy, iso'propoxy, butoxy, sec—butoxy, isobutoxy, t-butoxy, etc.— 6 alkoxy groups; methoxycarbonyl, ethoxycarbonyl, propoxy Alkoxyl groups such as isopropoxy, isopropoxy, butoxycarbonyl and t-butoxycarbonyl; nitro group; amino group; monomethylamino group; dimethylamino group or halogen atom such as fluorine, chlorine, bromine, and iodine; m represents 0 or an integer of 1 to 4, and when m is 2 or more, R i may be the same or different;
  • n represents an integer of 0 or 1 to 1 0, when n is 2 or more, R 2 to each other may be the same or different,
  • o represents an integer of 1 or 2
  • p represents 0 or an integer of 1 to 4, and when p is 2 or more, may be the same or different;
  • q, and r each independently represent an integer of 1 or 2
  • Y represents a substituent that satisfies the valence or a carbon atom or a nitrogen atom that may have a multiple bond
  • ⁇ represents a carbon atom
  • ⁇ represents an oxygen atom, a sulfur atom or the following formula (la);
  • R M is a hydrogen atom; (trialkylalkylcarbonyl group; (nitro group; fluorine, chlorine, bromine, iodine, etc.), hydroxyl group; methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- butoxy, isobutoxy, t-butoxy sheets or the like ( ⁇ - 6 alkoxy group; or methyl, Echiru, n-propyl, isopropyl, n- heptyl, sec one heptyl, Isopuchiru, t - and butyl Purukiru group;.
  • R 7 and R 8 each independently represent a hydrogen atom; a cyano group; a hydroxyl group; halogen atoms such as fluorine, chlorine, bromine, and iodine; methyl, ethyl, and the like.
  • C-e alkyl groups such as n-propyl, isopropyl, n-butyl, sec-butyl, isoptyl, and t-butyl; methoxy, ethoxy, propoxy, iso Alkoxy groups such as ropoxy, butoxy, sec-butoxy, isobutoxy, t-butoxy; ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl- 2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-1 C 2 _ 6 alkenyl groups such as xenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; ethynyl, 1-propynyl, 2-propy
  • C 2 - 6 Arukeniruokishi group 2-propynyl O carboxymethyl, 2-butynyl Okishi, 1-methyl-2-propynyl O carboxymethyl C 2 _ 6 Arukiniruokishi group and the like; ⁇ Setokishi, propionic necked alkoxy, Buchirirokishi Ashiruokishi group such as;
  • G 2 may cyclopropyl be substituted with, 1-methylcyclopropyl, 2-Mechirushi black-propyl, 2, 2-dimethyl-cyclopropyl, cyclobutyl, cyclopentyl Le, ⁇ 3 _ of cyclohexyl like cyclohexane 6 represents a cycloalkyl group; or a phenyl group optionally substituted with G 2;
  • j and k independently represent an integer of 0 or 1, and when B is (B-2), j and k represent 0;
  • R 7 and R 8 may be the same or different.
  • D represents an oxygen atom, a sulfur atom or the following formula (1a),
  • X is an oxygen atom, Formula: SOti (where u represents an integer of 0, 1 or 2) or Formula: NR 9 (where R 9 is a hydrogen atom, and may be substituted with G 2 represents or optionally substituted benzyl group in G 2 a table to); butyl, se c- butyl, Isobuchiru, d_ 6 alkyl group such as t- butyl - methyl, Echiru, n- propyl, isopropyl, n. ,
  • Z is a chroman-2-yl group substituted with G 3, a chroman-4-yl group substituted with G 3, a 2,3-dihydrobenzozofuran-1-yl group substituted with G 3, G 2,3-dihydrobenzofuran-3-yl group substituted with 3, thiochroman-12-yl group substituted with G3, 2,3-dihydrobenzothiophene-2 substituted with G3 —Yl group, thiochroman substituted with G 3-4-yl group, 2,3-dihydrobenzothiophene substituted with G 3 —3-yl group, or 1,3-benzozthiol substituted with G3 — Represents a 2-yl group,
  • Z include the following formulas (Z-1), (Z-2), (Z-3), (Z-4) and (Z-5).
  • * represents an asymmetric carbon atom, represents an oxygen atom or a sulfur atom, and R 12 to R 32 each independently represent a hydrogen atom; or methyl, ethyl, ii-propyl, isopropyl, It represents a; n - 6 alkyl group - butyl, sec- butyl, Isopuchiru, t one-butyl or the like.
  • G 3 has the formula: NHR 10
  • R 10 is a hydrogen atom; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy, butoxycarbonyl, alkylcarbonyl group such as t-butoxycarbonyl, etc .; (nitro group; fluorine, chlorine, bromine, iodine, etc. A hydroxyl group; —6 alkoxy group; or ( ⁇ -6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isoptyl, t-butyl, etc.) Or a benzoyl group. ⁇ Or a formula: ORRIERIE
  • R n is a hydrogen atom; methoxy Cal Poni Le, ethoxy Cal Poni Le, Provo Kishikaruponiru, isopropoxy, butoxide deer Lupo cycloalkenyl, t-Butokishikarupo two Le etc.
  • the compound wherein B is B-1 can be produced, for example, by the following production methods 1 to 7.
  • step 1 the carboxylic acid represented by the formula (3) and the amine represented by the formula (2) are dehydrated and condensed by an ordinary method to obtain a compound represented by the formula ( ⁇ ) (where A, E, Y , Rl, R2, m, n and o represent the same as A, E, Y, Rl, R2, m, n and o in the formula (2), respectively, and D 'and Z' represent the formula (3 ) Represents the same group as D ′ and Z ′ in).), Whereby the phenylazole compound of the present invention can be obtained.
  • This dehydration condensation reaction can be carried out in the presence of a suitable condensing agent.
  • the condensing agent include 1,3-dicyclohexylcarboimide, 1- (3-dimethylaminopropyl) -13-ethylcarboimide, 2-ethoxy-1-ethoxycarbonyl-1,2- Dihydroquinoline and the like can be used.
  • N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3,4-dihydro-3-hydroxy-4-oxo were added to the reaction system.
  • 1,2,3-benzotriazine By coexisting with 1,2,3-benzotriazine, the reaction can proceed more quickly.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include ethers such as getyl ether, tetrahydrofuran (hereinafter abbreviated as THF), 1,4-dioxane, benzene, Aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, acetonitrile, dimethylformamide (hereinafter abbreviated as DMF), dimethyl sulfoxide (hereinafter abbreviated as DMF) DM SO), pyridine and the like.
  • the reaction is carried out at a temperature of from 115 ° C to the boiling point of the solvent, preferably from 0 to 80 ° C.
  • -Production method 2 is carried out at a temperature of from 115 ° C to the boiling point of the solvent, preferably from 0 to 80 ° C.
  • a carboxylic acid derivative represented by the formula (3 ′) is converted to an acid chloride (4) using a halogenating agent such as thionyl chloride, phosphorus pentachloride, and oxalic acid dichloride.
  • a halogenating agent such as thionyl chloride, phosphorus pentachloride, and oxalic acid dichloride.
  • an inert appetizer solvent in the presence of a base, react with an amine represented by the formula (2), and formula ( ⁇ ) (where A, E, Y, Rl, R2, m, n and o Is the same as A, E, Y, Rl, R2, m, n and o in equation (2), respectively.
  • D ′ and Z ′ represent the same groups as D ′ and Z ′ in Formula (3), respectively.
  • the phenylazole compound of the present invention represented by the following formula (1) can be obtained.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction.
  • the reaction solvent include ethers such as dimethyl ether, THF, 1,4-dioxane and the like, and benzene, toluene, xylene and the like.
  • Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMS0, pyridine and the like can be used.
  • Examples of the base used in the reaction include amines such as triethylamine, pyridine, 1,8-diazapicyclo [5.4.0] indene-7-ene (hereinafter abbreviated as DBU), sodium hydrogen carbonate, and sodium carbonate. And inorganic bases such as potassium carbonate and sodium hydroxide.
  • amines such as triethylamine, pyridine, 1,8-diazapicyclo [5.4.0] indene-7-ene (hereinafter abbreviated as DBU), sodium hydrogen carbonate, and sodium carbonate.
  • inorganic bases such as potassium carbonate and sodium hydroxide.
  • the reaction is carried out at a temperature of about 15 ° C to about the boiling point of the solvent, preferably 0 to 80 ° C.
  • Production method 3 :
  • A, E, Y, Rl, R2, m, n and o are the same as A, E, Y, Rl, R2, m, n and o in the formula (1), respectively.
  • D ' is equivalent to D in the formula (1), and the equivalent between D and the formula CH 2 — D' holds.
  • Z ' is the same as the formula: (Z— 1), (Z-2), (Z-3), (Z-4) or (Z-5) represents Z when G 3 is a nitro group or ORterrorism.
  • the aldehyde represented by the formula (5) and the amine represented by the formula (2) are subjected to reductive amination by an ordinary method to obtain a compound represented by the formula (′) (where A, E, Y, Rl, R2, m, n and o are the same as A, E, Y, Rl, R2, m, n and o in the formula (2), respectively, and D 'and Z are D in the formula (5). 'And Z' And each represents the same group.
  • the phenylazole compound of the present invention represented by the formula (1) can be obtained.
  • This reductive amination reaction can be carried out by adding a reducing agent in the presence of a suitable acid catalyst.
  • a suitable acid catalyst include organic acids such as acetic acid and p-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.
  • the reducing agent include Na BH 4 and sodium triacetoxy borohydride.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include ethers such as diethyl ether, THF, and 1,4-dioxane, and aromatic solvents such as benzene, toluene, and xylene.
  • ethers such as diethyl ether, THF, and 1,4-dioxane
  • aromatic solvents such as benzene, toluene, and xylene.
  • Examples include hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMSO, pyridine and the like. .
  • the aniline compound which is the phenylazole compound of the present invention can be produced by the following method.
  • A, E, Y, Rl, R2, m, n and o are the same as A, E, Y, Rl, R2, m, n and o in the formula (l), respectively.
  • Z represents the same as above, when G3 in the above formula: (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5) is a nitro group Represents Z.
  • Step 2 the phenylazole compound of the present invention having a nitro group represented by the formula ( ⁇ ′) obtained by the above Production Methods 1 to 3 is subjected to hydrogenation using a catalyst.
  • an aniline compound which is a phenylazole-based compound of the present invention represented by the formula (1) and in which the nitro group of the substituent G 3 in Z ′ is NHR 10 is obtained.
  • Examples of the catalyst include palladium carbon, platinum dioxide, Raney nickel and the like.
  • reaction solvent examples include alcohols such as methanol and ethanol, ethers such as getyl ether, THF and 1,4-dioxane, hydrocarbons such as benzene, toluene, xylene and cyclohexane, and amides such as DMF.
  • Organic acids such as formic acid and acetic acid, esters such as ethyl acetate, and a mixed solvent thereof can be used.
  • A, E, Y, R1, R2, m, n and o in the formula (1 ',) are A, E, Y, Rl, R2, m, n and o in the formula (1).
  • Z ' represents the above formula: (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5) wherein G3 is a nitro group. Represents Z when. ⁇
  • Examples of the metal catalyst include stannous chloride.
  • Examples of the acid include sulfuric acid and hydrochloric acid.
  • Reaction solvents include alcohols such as methanol and ethanol; Ethers such as ter, THF, 1,4-dioxane and the like, hydrocarbons such as benzene, toluene, xylene and cyclohexane, amides such as DMF and the like, and a mixed solvent thereof can be used.
  • A, E, R1, R2, m, n, and o in Formula (1c,) are the same as A, E, R1, R2, m, n, and o in Formula (7a), respectively.
  • D represents the same group as D in the formula (1)
  • Z ' represents the above formula: (Z-1), (Z-2), (Z-3), (Z-1 4) or G3 in (Z-5) represents Z when it is a nitro group or OR.
  • E, Rl, R2, m, n and o represent the same as E, Rl, R2, m, n and o in the formula (1), respectively, and Y represents a carbon atom.
  • R 34 represents an acyl group
  • R 33 represents a halogen atom.
  • R4 and s represent the same as R4 and s in the formula (A-1), respectively.
  • A, E, R 1, R2, m, n, R 34 and o represent A in the formula (6)
  • A is the formula (gamma b) Represents an imidazolyl group derived from
  • A, E, R1, R2, m, n and o represent the same as A, E, R1, R2, m, n and o in the formula (7), respectively.
  • D represents the same group as D in the formula (1)
  • Z ′ represents the above formula: (Z-1), (Z-2), (Z-3), (Z-4 ) or G3 is the (Z- 5), it represents a Z when the nitro group or oR i, R 34 represents a par full O b alkyl group.
  • the phenylazole compound represented by the formula (1 c ′) is produced by reacting a compound represented by the formula (6) with an imidazole compound represented by the formula (b) in a solvent in the presence of a catalyst.
  • examples of the acetyl group represented by R 34 include an acetyl group, a propionyl group, and a butyryl group, and the halogen atom represented by R 33 Examples thereof include a bromine atom, a chlorine atom, a fluorine atom, an iodine atom and the like.
  • the reaction between the imidazole compound or the imidazole compound represented by the formula (b) having such a group is Catalysts such as 1,10-phenanthroline, 1,5-diphenyl-1,4-pentagen-13-one, cesium carbonate and trifluoromethanesulfonate (I) ) It can be performed using a benzene complex or the like.
  • the reaction is carried out by heating and refluxing in a stream of argon at a temperature corresponding to the boiling point of the solvent, such as 100 to 150 ° C, to obtain a product represented by the formula (7).
  • the reaction product represented by the formula (7) can be dehydrated by heating and refluxing with concentrated hydrochloric acid or the like. After the reaction, the reaction product is neutralized with an alkali, and is then represented by the formula (7a).
  • Catalysts such as 1,10-phenanthroline, 1,5-diphenyl-1,4-pentagen-13-one, cesium carbonate and trifluoromethan
  • perfluoroalkanesulfonic acid ester compound represented by the formula (8) used in the step 2 those having a trifluoromethyl group, a perfluoroethyl group or the like as R 35 can be mentioned.
  • a trifluoromethyl group is preferred.
  • Such a perfluoroalkanesulfonic acid compound and the compound obtained in Step 1 The reaction with the compound represented by the formula (7a) is carried out in a solvent such as acetonitrile, dioxane, an ether-based solvent such as THF, or a BTX-based solvent such as benzene or toluene. It can be carried out by heating and refluxing at 100 to 150 ° C. using a base such as described above. Production method 7:
  • the aniline compound which is the phenylazole compound of the present invention can be produced by the following method. Process 3:
  • A, E, Y, R1, R2, m, n, and o are A, E, Y, R1, R2, m in the formula (1c '). , N and o, respectively, and Z represents a group in which the substituent G 3 has become NHR 10 in Z ′ in the formula (lc ′).
  • A, E, Y, R1, R2, m, n and o are the same as A, E, Y, Rl, R2, m, n and o in the formula (1c). Each represents the same thing.
  • the phenylazole compound having a nitro group represented by the formula (1c ′) obtained in the step 2 is reduced, and the nitro group of the substituent G 3 in Z ′ becomes NH R 10.
  • a phenylazole compound represented by the formula (1c) is carried out in an acidic solution using a catalyst such as stannous chloride dihydrate in an acidic solution at a temperature of 100 to 150 ° C. After completion of the reaction by heating to reflux at a temperature, a method of neutralizing the mixture with an alkali can be used.
  • reaction of reducing the phenylazole-based compound represented by (lc) obtained in Step 3 to obtain a phenylazole-based compound represented by formula (Id) is carried out by using palladium carbon or the like.
  • Alcohols such as methanol and ethanol, acetic acid, etc.
  • Hydrogenation can be performed in a solvent such as an organic acid or a mixed solvent thereof at room temperature or at 0 to 60 ° C.
  • the 3-imidazole compound can be synthesized in the same manner as described above.
  • the amide type can also be synthesized in a similar manner.
  • the compound wherein the B part is (B-2) can be produced, for example, as shown in the following production methods 8 to 11. Production method 8:
  • A, Rl, 119 and 111 represent the same as A, Rl, R9 and m in the formula (1), respectively.
  • D ' is the formula (1)
  • D in the equivalence between D and the formula CH 2 —D 'holds
  • Z' represents Z in G in formula (1) when G3 is a nitro group or ORu.
  • the phenylazole derivative (1) of the present invention represented by the formula (1) is subjected to a reductive amination reaction by a conventional method. e) is obtained.
  • Such a reductive amination reaction can be carried out by adding a reducing agent in the presence of a suitable acid catalyst.
  • the acid catalyst include organic acids such as acetic acid and P-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.
  • the reducing agent include NaBH 4 , sodium triacetoxyborohydride and the like.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include ethers such as dimethyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Examples include hydrogens, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMSO, pyridine and the like.
  • the reaction can be carried out at a temperature of about 15 ° C. to about the boiling point of the solvent, preferably at room temperature.
  • Production method 9 :
  • the phenylazole derivative represented by the formula (1) of the present invention can be produced, for example, as follows.
  • A, R 1, m and X represent the same as A, R l, m and X in the formula (1), respectively, and in the formula (10 ′), D represents the formula (1) Has the same meaning as D in formula (1), Z ′ represents Z in formula (1) and G 3 represents nitro group or ORtown, and R 36 represents a leaving group derived from alcohol, chlorine, bromine, Represents halogens such as iodine, and sulfonic esters such as methanesulfonate, toluenesulfonate, and trifluoromethanesulfonate.
  • the compound represented by the formula (9 ′) is alkylated using the compound represented by the formula (10 ′), and the compound which is the phenylazole derivative represented by the formula (1) of the present invention is obtained. (L e ').
  • Such reactions include ethers such as getyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; and halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane.
  • ethers such as getyl ether, THF, and 1,4-dioxane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane.
  • Acetonitrile Toluene, DMF, DMSO in an inert solvent in the presence of bases such as amines such as triethylamine, pyridine and DBU, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and sodium hydroxide at 15 ° C To about the boiling point of the solvent, preferably from 0
  • 41- (imidazolyl-11-yl) thiophenol represented by the formula (6 ') can be produced by a known method described in the literature (for example, German Patent Application Publication No. 2267101). Can be.
  • Production method 10: '-The phenylazole derivative of the present invention represented by the formula (1) can be produced, for example, as shown in the following formula.
  • R 9 represents the same meanings as R 9 in the formula (1), the formula (9 Formula (10)' in '), A, R l, m and D A in the formula (1), R l, represent respectively m and D identical, Z 'in Z in the formula (1), G 3 represents a Z when the nitro group or oR n group, wherein (10 "), R 37 is de A leaving group represents a halogen such as chlorine, bromine or iodine, or a sulfonic acid ester such as methanesulfonate, toluenesulfonate or trifluoromethanesulfonate. ⁇
  • the compound represented by the formula (9 '') is alkylated using the compound represented by the formula (10 ''), and the compound (I) which is a phenylazole derivative represented by the formula (1) of the present invention ( l e '').
  • Such reactions include ethers such as getyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as loroform and 1,2-dichloroethane, etc., in inert solvents such as acetonitrile, DMF and DMSO, amines such as triethylamine, pyridine and DBU, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and sodium hydroxide
  • a base such as an inorganic base such as lium at a temperature of from 115 ° C to about the boiling point of the solvent, preferably from 0 to 100 ° C.
  • the phenylazole derivative of the present invention represented by the formula (1) can be produced, for example, as shown in the following formula.
  • A, R1, m, D and X represent the same as A, R1, m, D and X in the formula (1), respectively, and Z' represents the formula (1) Represents Z when G3 is a two-terminal group.
  • the nitro compound represented by the formula (1 e ′′ ′) is hydrogenated using a catalyst or reduced using a reducing agent to obtain a compound represented by the formula (1) of the present invention.
  • the nitro group of the substituent G 3 in Z ′ is NHRi.
  • An aniline compound (1f) of the phenylazole derivative is obtained.
  • Examples of such a hydrogenation catalyst include palladium carbon, palladium hydroxide, platinum dioxide, Raney nickel and the like.
  • reaction solvent examples include alcohols such as methanol and ethanol, ethers such as getyl ether, THF and 1,4-dioxane, hydrocarbons such as benzene, toluene, xylene and cyclohexane, and amides such as DMF.
  • Organic acids such as formic acid and acetic acid, esters such as ethyl acetate, and mixed solvents thereof can be used.
  • reduction is performed using acetic acid and iron in an alcohol such as methanol or ethanol, using hydrochloric acid and stannous chloride, or in a mixed solvent of acetone, methyl ethyl ketone, etc. and water. be able to.
  • the reaction can be performed at 0 ° C. to about the boiling point of the solvent.
  • the desired product after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.
  • the compound represented by the above formula (1) in which part B is (B-3) can be produced, for example, by the following production methods 12 to 15. it can.
  • the carboxylic acid derivative represented by the formula (3) is converted to an acid chloride (4) by using a halogenating agent such as thionyl chloride, phosphorus pentachloride, and oxalic acid dichloride.
  • a halogenating agent such as thionyl chloride, phosphorus pentachloride, and oxalic acid dichloride.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction.
  • examples include ethers such as getyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMSO, pyridine and the like can be used.
  • Examples of the base used in the reaction include amines such as triethylamine, pyridine and DBU, and inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate and sodium hydroxide.
  • the reaction is carried out at a temperature of about 15 ° C to about the boiling point of the solvent, preferably 0 to 80 ° C.
  • Production method 13 :
  • A, Rl, R3, p, q and r represent the same as A, R1, R3, p, q and r in the formula (1), respectively, and the formula (3)
  • Z 'is Z in the formula (1) and G 3 is a nitro group or Represents Z for OR u. That is, an amide derivative which is a nitro compound represented by the formula (lg) is obtained by subjecting a carboxylic acid represented by the formula (3) and an amamine represented by the formula (11) to dehydration condensation by a conventional method. It is.
  • This dehydration condensation reaction can be carried out in the presence of a suitable condensing agent.
  • the condensing agent include 1,3-dicyclohexylcarboimide, 1- (3-dimethylaminopropyl) -13-ethylcarboimide, 2-ethoxy-11-ethoxycarbonyl-1,2 —Dihydroquinoline and the like.
  • N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine must be present in the reaction system. This allows the reaction to proceed more quickly.
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction.
  • examples thereof include ethers such as getyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene.
  • examples include hydrogens, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetate nitrile, DMF, DMS ⁇ , and pyridine.
  • the reaction is carried out at from ⁇ 15 ° C. to about the boiling point of the solvent, preferably from 0 to 80 ° C.
  • the compound represented by the general formula (2) can be synthesized by a known method described in the literature [for example, Journal of Medicinal Chemistry, 1989, Vol. 23, p. — 643, Synthesis, 1977, P. 645—6464, Journal of Medicinal Chemistry, 1977, 20th Vol., P. 600-602 etc.]. Manufacturing method 14:
  • This reductive amination reaction can be carried out by adding a reducing agent in the presence of a suitable acid catalyst.
  • a suitable acid catalyst include organic acids such as acetic acid and P-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.
  • the reducing agent include sodium borohydride and sodium triacetoxy hydride. '. 1
  • the reaction solvent is not particularly limited as long as it is a solvent inert to the reaction.
  • the reaction solvent include ethers such as getyl ether, THF, 1,4-dioxane and the like, benzene, toluene, xylene and the like.
  • ethers such as getyl ether, THF, 1,4-dioxane and the like, benzene, toluene, xylene and the like.
  • aromatic hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetate nitrile, DMF, DMS ⁇ , and pyridine.
  • the reaction is carried out at a temperature of about 15 ° C. to about the boiling point of the solvent, preferably at room temperature.
  • an aniline compound represented by the formula (1j) is obtained by hydrogenating a nitro compound represented by the formula (1i) such as the formulas (lg) and (1h) using a catalyst. .
  • Examples of the catalyst include palladium carbon, platinum dioxide, Raney nickel and the like.
  • reaction solvent examples include alcohols such as methanol and ethanol; ethers such as getyl ether, THF and 1,4-dioxane; hydrocarbons such as benzene, toluene, xylene and cyclohexane; and amides such as DMF.
  • Organic acids such as acetic acid, formic acid, and acetic acid, esters such as ethyl acetate and the like, and a mixed solvent thereof can be used.
  • the reaction is carried out at 0 ° C. to about the boiling point of the solvent, preferably at 20 to 80 ° C.
  • the desired product can be obtained by performing ordinary post-treatment.
  • the structure of the compound of the present invention was determined from IR, NMR, MS and the like.
  • the phenylazole compound of the present invention represented by the formula (1) may have several optically active forms and tautomers. These are all included in the scope of the present invention.
  • the pharmaceutically acceptable salt of the phenylazole compound represented by the formula (1) of the present invention is not particularly limited as long as it is a salt of the phenylazole compound represented by the formula (1) and is pharmaceutically acceptable.
  • Such salts include, but are not limited to, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, cunic acid, benzoic acid, and salicylic acid.
  • salts of organic acids such as nicotinic acid and heptagluconic acid. These can be easily produced by ordinary synthetic chemistry techniques.
  • the phenylazole compound of the present invention has an antioxidant effect, it has a low specific gravity.
  • LDL low density lipoprotein
  • it can prevent the development and progression of atherosclerotic lesions, and can be used as a therapeutic drug for atherosclerosis. It is also useful as a therapeutic agent for various diseases based on oxidative action, such as aging, dementia disease, heart disease, cancer, diabetes, digestive diseases, burns, eye diseases, and kidney diseases.
  • ischemic organ diseases such as cerebral infarction and myocardial infarction
  • various active oxygens are generated during blood reperfusion at the ischemic site, and tissue damage is exacerbated by cell membrane rupture due to lipid peroxidation.
  • the phenylazole compound of the present invention can remove various active oxygens and lipid peroxides by its antioxidant activity, can prevent tissue damage at ischemic lesions, and can be applied to a therapeutic drug for ischemic organ damage.
  • the phenylazole compound of the present invention has a lipoxygenase inhibitory action and a 20-HETE synthase inhibitory action, and inhibits the conversion of arachidonic acid to HPETE by inhibiting the action of lipoxygenase.
  • 20-HETE synthase by inhibiting 20-HETE synthase, production of 20-HETE can be suppressed.
  • compounds having a small dopamine release inhibitory action and a low possibility of causing side effects such as Parkinson's are also included.
  • the phenylazole compound of the present invention can be used for connective tissues such as diseases caused by oxidative disorders of the retina, diabetes, hypertension, arteriosclerosis, anemia, leukemia, systemic lupus erythematosus and scleroderma.
  • Diseases retinal vascular disorders, inflammatory and degenerative diseases caused by systemic diseases such as inborn errors of metabolism such as Tay-S acks disease and Vogt-Schmeyer disease Lesions
  • retinal disorders such as retinopathy of prematurity, retinal vein occlusion, retinal artery occlusion, retinal periphleitis, retinal inflammation or degeneration caused by retinal detachment or trauma, age-related macular degeneration, etc. It can be used for the prevention and treatment of retinal degenerative diseases associated with aging and congenital retinal degenerative diseases, especially age-related macular degeneration and diabetic retinopathy caused by photooxidation disorders. As a treatment for diseases It is a use.
  • the antioxidant of the present invention is not particularly limited as long as it contains one or more of the phenylazole compounds of the present invention having the above-mentioned antioxidant action or a pharmaceutically acceptable salt thereof as an active ingredient.
  • It can be administered by formula.
  • it can be administered orally, nasally, parenterally, topically, dermally or rectally, and may be in the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as tablets, suppositories, pills , Soft and hard capsules, powders, solutions, injections, suspensions, aerosols, sustained-release preparations, etc., which can be formulated into precise dosages and can be administered easily. It can be in dosage form.
  • the antioxidant of the present invention can be made into a composition containing an active ingredient, a conventional pharmaceutical carrier or excipient, other drugs, an adjuvant, and the like in a range that does not react with other components.
  • Such compositions may contain from 1 to 99% by weight of the active ingredient and 99 to 1% by weight of a suitable pharmaceutical carrier or excipient, depending on the mode of administration. 5 to 75% by weight, with the balance being a suitable pharmaceutical carrier or excipient.
  • the antioxidant of the present invention may optionally contain a small amount of auxiliary substances, such as wetting agents, emulsifiers, pH buffers, antioxidants, etc.
  • auxiliary substances such as wetting agents, emulsifiers, pH buffers, antioxidants, etc.
  • Cuenic acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene and the like can also be added.
  • Formulations such as, for example, Remington's Pharmaceutical Sciences, 18th ed., Mac'Pub Lishing Campaign, Easton, Pa. (Mack Publishing Co. any, Eas ton, Pennsylvania) can be produced according to the description taught in 1990 and the like.
  • the therapeutically effective amount of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof varies depending on the individual and the disease state to be treated.
  • the therapeutically effective daily dose is 0.14 mg to 14.3 mg / kg of the compound represented by the formula (1) or one or more pharmaceutically acceptable salts thereof per kg of body weight. It can be 0.7 mg to 10 mg ZB / kg body weight, more preferably 1.4 mg to 7.2 mg / kg body weight / day.
  • the dose range of the compound of the formula (1) or a pharmaceutically acceptable salt thereof is 10 mg to 1.0 g per day, preferably one day. 50 mg to 700 mg, more preferably 1 day It will be between 100 mg and 500 mg, but this is only a guide and may be outside of this range depending on the condition of the treatment.
  • the preferred route of administration of the antioxidant of the present invention is oral, and the excipient applied to the oral antioxidant includes any commonly used excipient, for example, mannitol for pharmaceutical use. , Lactose, starch, gelatinized starch, magnesium stearate, sodium saccharine, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like.
  • Oral antioxidants include diluents, for example, lactose, sucrose, diphosphate phosphate, etc., as disintegrants, for example, croscarmellose sodium or derivatives thereof, as binders, and the like.
  • magnesium stearate and the like can be contained as a lubricant, for example, starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether derivative and the like.
  • the antioxidant of the present invention when used as an injection, it is preferable to include a sterile aqueous or non-aqueous solution, suspension, or emulsion.
  • a sterile aqueous or non-aqueous solution, suspension, or emulsion for example, distilled water for injection and physiological saline can be used.
  • a diluent for a water-insoluble solution or suspension for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate (trade name) and the like can be used. .
  • Such injections may further contain additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing or solubilizing agents.
  • additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing or solubilizing agents.
  • a carrier that gradually dissolves in the body as a carrier for example, polyoxyethylene glycol or polyethylene glycol (hereinafter abbreviated as PEG), specifically, PEG Using 100 (96%) or PEG 400 (4%), 0.5 to 50% by weight of a compound of the formula (1) or a pharmaceutically acceptable salt thereof is added to such a carrier. Dispersed materials can be mentioned.
  • antioxidant of the present invention When the antioxidant of the present invention is used as a liquid, water, saline, dextrose may be used as a carrier.
  • An aqueous pharmaceutical solution, glycerol, ethanol, or the like is used, and the compound of the formula (1) or a pharmaceutically acceptable salt thereof is added to such a carrier together with 0.5 to 50% by weight, and an arbitrary pharmaceutical adjuvant is added.
  • a solution or suspension that has been subjected to treatments such as dissolution and dispersion is preferred.
  • the retinal oxidative damage inhibitor of the present invention is an antioxidant containing, as an active ingredient, one or more of the phenylazole compound of the present invention or the pharmaceutically acceptable salt thereof having the above-mentioned antioxidant action. It is not particularly limited as long as it contains the antioxidant, and the administration mode, administration form, and dosage can be the same mode, form, and dosage as those of the above-mentioned antioxidant. Pharmaceutical ingredients, carriers, adjuvants, etc. similar to drugs can be included, and one or more excipients, disintegrants, binders, and other retinal oxidative damage inhibitors that do not react with the active ingredient May be appropriately added, and in addition to the above, other components having other medicinal effects may be appropriately contained.
  • the dosage form can be an eye drop or an ointment in addition to the same dosage form as in the above-mentioned antioxidant.
  • the phenylazole compound of the present invention is added to a commonly used base solvent to form an aqueous solution or suspension, and PH is preferably 4 to 10, preferably. Can be adjusted from 5 to 9.
  • the ophthalmic solution is preferably subjected to a sterilization treatment to make it a sterile product, and such a sterilization treatment can be performed at any stage of the production process.
  • the concentration of the phenylazole compound of the present invention in the eye drops is 0.01 to 3% (wzv), preferably 0.01 to 1% (W / V).
  • several drops can be made 1 to 4 times a day. The above dose is only a guideline until it gets tired, and it can be administered beyond this range.
  • a buffer such as a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid.
  • examples of the isotonic agent include saccharides such as sorbitol, glucose, and mannitol, and glycerin. , Examples thereof include polyhydric alcohols such as polyethylene glycol and propylene glycol, and salts such as sodium chloride and the like.
  • preservatives include, for example, paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl ethyl laoxybenzoate. Benzyl alcohol, phenethyl alcohol, sorbic acid or a salt thereof, and the like.
  • pH adjuster include phosphoric acid and sodium hydroxide
  • examples of the thickener include Examples thereof include hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.
  • the chelating agent include sodium edetate and citrate. Sodium, condensed phosphorus Can be mentioned sodium, etc.
  • solubilizing agent for example, ethanol, can be given polio Kishechiren hydrogenated castor oil and the like.
  • the phenylazole compound of the present invention is usually used as an ointment base such as purified lanonone, white serine, macrogol, and plastibase. , Liquid paraffin or the like, and preferably sterilized to obtain a sterile product.
  • the concentration of the phenylazole compound of the present invention in the ophthalmic ointment is 0.01 to 3% (W / W), preferably 0.01 to 1% (W / W). It can be 1 to 4 times a day depending on various conditions such as the degree of the disease and the constitution of the patient. The above dose is a guide to the extent of getting tired, and it is possible to administer beyond this range.
  • the retinal oxidative damage inhibitor of the present invention has an excellent antioxidant activity, it is effective for preventing and treating aging-related retinal degenerative diseases such as age-related macular degeneration and diabetic retinopathy. is there.
  • the lipoxygenase inhibitor, 20-hydroeicosatetraenoic acid (20-HETE) synthase inhibitor, renal disease, cerebrovascular or circulatory disease therapeutic agent, and cerebral infarction therapeutic agent of the present invention have the above-mentioned antioxidant effect.
  • the form, dosage form, and dosage can be the same form, form, and dosage as those of the above-mentioned antioxidant, and can include the same ingredients for formulation, carrier, adjuvant, etc. as those of the above-mentioned antioxidant.
  • Can, Excipients, disintegrants, binders, and other retinal oxidative damage inhibitors that do not react with the active ingredient
  • the dosage form can be the same dosage form as in the case of the above antioxidant.
  • (S) 1 (5-two-trough 2,4,6,7-tetramethyldihydrobenzophenfuran-2-yl) 1 [4- (4-imidazolu 1-ylphenyl) 1-piperazine 1 [10]
  • Ethanol (10 ml) and acetic acid (5 ml) were added to 0.88 g and 0.5 g of 10% palladium carbon, and the mixture was stirred at a hydrogen pressure of 10 kg / cm 2 .
  • the reaction solution was poured into water, neutralized with IN sodium hydroxide solution, and extracted with chloroform.
  • the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the 3-imidazole compound can be synthesized in a similar manner.
  • the amide type can also be synthesized in the same manner.
  • Step 1 Preparation of 4- (1-)-1- (5-nitro-1,2,4,6,7-tetramethyldihydrobenzofuran-1-ylmethyl) aminophenyl-1-imidazole
  • Step 1 Preparation of 5- (4- (Sat) -I (5-Tiitrol 2,4,6,7-Tetramethyldihydro-drobenzofuran-1-ylmethyl) aminophenyl) pyrazole
  • the organic layer was washed with aqueous hydrochloric acid, neutralized with an aqueous sodium hydroxide solution, and the organic layer was washed with saturated saline. Thereafter, the extract was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 1.5 g of the desired product.
  • Step 3 3 (5)-(4- (Ph)-(5-nitro-1,2,4,6,7-tetramethyldihydrobenzofuran-1-ylmethyl) methylaminophenyl) — 1— ( Preparation of trahydropyran-1-yl) pyrazole
  • Step 1 Preparation of 2,4,6,7-tetramethyl-1-nitrodihydrobenzofuran-12-trifluoromethanesulfonate 6.7 g of trifluoromethanesulfonic anhydride was dissolved in 5 Oml of dichloromethane and cooled to 0 ° C. In the solution, 5.0 g of 2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran and 2.4 g of triethylamine dissolved in 5 Om 1 of dichloromethane were added dropwise over 30 minutes. After the dropwise addition, the mixture was stirred at 0 ° C. for 1 hour, and then heated to room temperature and further stirred for 1.5 hours.
  • Step 2 Preparation of 4- (Sat) -1- (5-nitro-1,2,4,6,7-tetramethyldihydrobenzofuran-1-ylmethoxy) -1-phenyl-1-imidazole
  • Process 3 4- (1-)-(5-amino-1,2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethoxy) 1-phenyl-1_imidazole
  • Step 1 (Sat) 2-(5-Nitro- 2, 4, 67-tetramethyldihydrobenzo-furan-1-ylmethyl) 2, 3, 4, 9 Tetrahydro- 1 H Production of ruporin
  • Step 1 ( ⁇ ) — (1,3,4,9-tetrahydrobecanylcarporin-21-yl) — (5-nitro-1,2,4,6,7-tetramethyldihydrobenzofuran-1-yl) ) Production of Methanone
  • the mixture was poured into ice-ice-water, and stirred at room temperature for 11 hours. .
  • the reaction solution was extracted with ether ether, washed with saturated saturated saline solution, washed and purified, and then dried and dried over anhydrous magnesium sulfate sulfate.
  • 6-Nitro-2-methoxymethyl-1,2,5,7,8-Tetramethylchroman 9.5 is dissolved in dimethyl chloride 8 Om 1 and 1M boron tribromide chloride solution at 0 ° C under nitrogen stream 31.4 ml was added, and the mixture was stirred at 0 ° C for 3 hours. After the completion of the reaction, the reaction solution was poured into water, and extracted with black form. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Tables 1 to 29 show specific examples of the compound of the present invention. For compounds with & NMR indicated in the physical constants in the table, NMR data is shown at the end of the table. Decomp. In the table represents the decomposition. Abbreviations and symbols in the table have the following meanings.

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Abstract

L'invention concerne des composés représentés par la formule générale (1) ou leurs sels pharmaceutiquement acceptables ainsi que des antioxydants, des remèdes contre les maladies du foie ou les troubles cérébrovasculaires, ou des inhibiteurs de détérioration rétinienne oxydative contenant les composés en tant que principes actifs : (1) B D Z où B est un groupe représenté par la formule générale suivante (B-1), (B-2) ou (B-3), A représente imidazolyle ou pyrazolyle ; E est un groupe représenté par la formule générale (1a) ou analogue : X représente O, SOu ou N-R9 ; Y représente carbone ou azote ; D représente oxygène, soufre ou un groupe de la formule générale (1a) ; Z représente un groupe chroman-2-yle, chroman-4-yle, 2,3-dihydrobenzofuran-2-yle ou 2,3-dihydrobenzofuran-3-yle à substitution NHR10 ou OR11.
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WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
WO2008099804A1 (fr) * 2007-02-14 2008-08-21 School Juridical Person Kitasato Institute Agent thérapeutique pour la cataracte diabétique
WO2009133701A1 (fr) * 2008-05-01 2009-11-05 日本曹達株式会社 Dérivé de phénylimidazole et agent thérapeutique et/ou prophylactique pour un trouble rétinien/choroïdien
US7638531B2 (en) * 2005-12-21 2009-12-29 Schering Corporation Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
WO2015002061A1 (fr) * 2013-07-04 2015-01-08 日本曹達株式会社 Dérivé de phénylimidazole, et médicament thérapeutique ou médicament préventif d'une maladie inflammatoire, etc.
JP2015522067A (ja) * 2012-07-12 2015-08-03 コンドリオン アイピー ビー．ブイ．Ｋｈｏｎｄｒｉｏｎ Ｉｐ Ｂ．Ｖ． ミトコンドリア病を治療するためのクロマニル誘導体
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
WO2019031618A1 (fr) * 2017-08-10 2019-02-14 大正製薬株式会社 Composé de pyridine substitué par un azole

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EP2240481A1 (fr) 2008-01-11 2010-10-20 Albany Molecular Research, Inc. Pyridoindoles (1-azinone)-substitués en tant qu'antagonistes mch
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WO2011003012A1 (fr) 2009-07-01 2011-01-06 Albany Molecular Research, Inc. Antagonistes de mch-1 azapolycycles substitués par azinone, leurs procédés de fabrication et leur utilisation
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US20110269807A1 (en) * 2010-04-30 2011-11-03 Allergan, Inc. Novel treatment for age related macular degeneration and ocular ischemic disease associated with complement activation by targeting 5-lipoxygenase
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WO2012088124A2 (fr) 2010-12-21 2012-06-28 Albany Molecular Research, Inc. Antagonistes de la mch-1 à base de tétrahydro-azacarboline, leurs procédés de fabrication et leurs utilisations
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WO2023185821A1 (fr) * 2022-03-31 2023-10-05 广州必贝特医药股份有限公司 Composé hétérocyclique aromatique ou à noyau aromatique substitué 1,4-dihétérocyclique ou et son utilisation
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US7638531B2 (en) * 2005-12-21 2009-12-29 Schering Corporation Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
WO2008099804A1 (fr) * 2007-02-14 2008-08-21 School Juridical Person Kitasato Institute Agent thérapeutique pour la cataracte diabétique
JP2008195655A (ja) * 2007-02-14 2008-08-28 Kitasato Institute 糖尿病白内障の治療剤
WO2009133701A1 (fr) * 2008-05-01 2009-11-05 日本曹達株式会社 Dérivé de phénylimidazole et agent thérapeutique et/ou prophylactique pour un trouble rétinien/choroïdien
JP2015522067A (ja) * 2012-07-12 2015-08-03 コンドリオン アイピー ビー．ブイ．Ｋｈｏｎｄｒｉｏｎ Ｉｐ Ｂ．Ｖ． ミトコンドリア病を治療するためのクロマニル誘導体
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
CN105324366A (zh) * 2013-07-04 2016-02-10 日本曹达株式会社 苯基咪唑衍生物以及炎症性疾病等的治疗药或预防药
JPWO2015002061A1 (ja) * 2013-07-04 2017-02-23 日本曹達株式会社 フェニルイミダゾール誘導体、および炎症性疾患などの治療薬若しくは予防薬
WO2015002061A1 (fr) * 2013-07-04 2015-01-08 日本曹達株式会社 Dérivé de phénylimidazole, et médicament thérapeutique ou médicament préventif d'une maladie inflammatoire, etc.
WO2019031618A1 (fr) * 2017-08-10 2019-02-14 大正製薬株式会社 Composé de pyridine substitué par un azole
CN110914254A (zh) * 2017-08-10 2020-03-24 大正制药株式会社 唑类取代的吡啶化合物
JPWO2019031618A1 (ja) * 2017-08-10 2020-07-30 大正製薬株式会社 アゾールで置換されたピリジン化合物
JP7052798B2 (ja) 2017-08-10 2022-04-12 大正製薬株式会社 アゾールで置換されたピリジン化合物
US11365192B2 (en) 2017-08-10 2022-06-21 Taisho Pharmaceutical Co., Ltd. Pyridine compound substituted with azole

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